Method of preparing phenoxy alkanoic, alkenoic, and alkynoic acids and salts thereof via a dicarboxylate intermediate

ABSTRACT

The present invention relates to a method of preparing a phenoxy alkanoic, alkenoic, or alkynoic acid or a salt thereof from a phenoxy containing compound via a dicarboxylate intermediate. The phenoxy alkanoic, alkenoic, and alkynoic acids and salts thereof prepared by this method are suitable for use in composition for delivering active agents via oral or other routes of administration to animals. Furthermore, the present invention relates to phenoxy dicarboxylic acids and their salts for delivering active agents, such as biologically or chemically active agents, to a target.

This application claims the benefit of U.S. Provisional Application No.60/325,657, filed Sep. 26, 2001, which is hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention relates to a method of preparing a phenoxyalkanoic, alkenoic, or alkynoic acid or a salt thereof from a phenoxycontaining compound via a dicarboxylate intermediate. The phenoxyalkanoic, alkenoic, and alkynoic acids and salts thereof prepared bythis method are suitable for use in compositions for delivering activeagents via oral or other routes of administration to animals.Furthermore, the present invention relates to phenoxy dicarboxylic acidsand their salts for delivering active agents, such as biologically orchemically active agents, to a target.

BACKGROUND OF THE INVENTION

International Publication No. WO 01/32596 discloses phenoxy alkanoic,alkenoic, and alkynoic acids and salts thereof for the delivery ofactive agents and methods for preparing the same.

Alternate methods of producing phenoxy alkanoic, alkenoic, and alkynoicacids and salts thereof would be useful, especially where raw materialsare expensive, yields are low, and reaction conditions are difficult.

Therefore, there is a need for simpler and less expensive methods ofpreparing phenoxy alkanoic, alkenoic, and alkynoic acids and saltsthereof.

SUMMARY OF THE INVENTION

The present invention relates to a method of preparing a phenoxyalkanoic, alkenoic, or alkynoic acid or a salt thereof from a phenoxycontaining compound via a dicarboxylated phenoxy containingintermediate.

The present invention includes a dicarboxylated intermediate having theformula

where

R¹, R², R³, and R⁴ are independently H, —OH, halogen, C₁-C₄ alkyl, C₂-C₄alkenyl, C₁-C₄ alkoxy, —C(O)R¹², —NO₂, —NR⁹R¹⁰, or —N⁺R⁹R¹⁰R¹³(R¹⁴)⁻;

R⁵ is H, —OH, —NO₂, halogen, —CF₃, —R¹⁵R¹⁶, —N⁺R¹⁵R¹⁶R¹⁷ (R¹⁸)⁻, amide,C₁-C₁₂ alkoxy, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, carbamate, carbonate, urea,or —C(O)R¹⁹;

R⁷is a linear or branched, C₁-C₂₀ alkylene, C₂-C₂₀ alkenylene, or C₂-C₂₀alkynylene;

R⁷ is optionally substituted with C₁-C₄ alkyl, C₁-C₄ alkenyl, oxygen,nitrogen, sulfur, halogen, —OH, C₁-C₄ alkoxy, aryl, heteraryl, or vinyl;

R⁷ is optionally interrupted with aryl, heteroaryl, vinyl, oxygen,nitrogen, or sulfur;

R⁸ and R¹¹ are independently C₁-C₄ alkyl or C₁-C₄ haloalkyl;

R⁹, R¹⁰, and R¹³ are independently H or C₁-C₁₀ alkyl;

R¹² is H, C₁-C₄ alkyl, C₂-C₄ alkenyl, or —NH₂;

R¹⁴ and R¹⁸ are independently a halide, hydroxide, sulfate,tetrafluoroborate, or phosphate;

R¹⁵, R¹⁶, and R¹⁷ are independently H, C₁-C₁₀ alkyl, C₁-C₁₀ alkylsubstituted with —COOH, C₂-C₁₂ alkenyl, C₂-C₁₂ alkenyl substituted with—COOH, —C(O)R²⁰;

R¹⁹ is —H, C₁-C₆ alkyl, or C₂-C₁₂ alkenyl; and

R²⁰ is —OH, C₁-C₁₀ alkyl, or C₂-C₁₂ alkenyl.

According to one preferred embodiment, R¹, R², R³, R⁴, and R⁵ areindependently hydrogen, hydroxy, halogen, and C₁-C₄ alkoxy; R⁷ is alinear or branched, C₁-C₂₀ alkylene, C₂-C₂₀ alkenylene, or C₂-C₂₀alkynylene; R⁷ is optionally substituted with C₁-C₄ alkyl, C₁-C₄alkenyl, oxygen, nitrogen, sulfur, halogen, —OH, C₁-C₄ alkoxy, aryl,heteraryl, or vinyl; R⁷ is optionally interrupted with aryl, heteroaryl,vinyl, oxygen, nitrogen, or sulfur; and R⁸ and R¹¹ are independentlyC₁-C₄ alkyl or C₁-C₄ haloalkyl.

According to another embodiment, R₁, R², R³, R⁴, and R⁵ are selectedfrom hydrogen, hydroxy, halogen, methoxy and ethoxy. According to yetanother embodiment, R⁷ is a C₇-C₁₂ alkylene and, more preferably, is alinear C₇-C₁₂ alkylene.

The dicarboxylated intermediate may be prepared by alkylating a phenoxycontaining compound with a dicarboxylate alkylating agent. In oneembodiment, the phenoxy alkanoic, alkenoic, or alkynoic acid is preparedby hydrolyzing the dicarboxylated intermediate. In another embodiment,the phenoxy alkanoic, alkenoic, or alkynoic acid is prepared bydecarboxylating the dicarboxylated intermediate. Optionally, thedicarboxylated intermediate can be hydrolyzed before or after beingdecarboxylated. Preferably, the dicarboxylated intermediate ishydrolyzed before undergoing decarboxylation. The phenoxy alkanoic,alkenoic, and alkynoic acids and salts thereof prepared by this methodare suitable for use in compositions for delivering active agents viaoral or other routes of administration to animals.

Many of the alkylating agents disclosed in the prior art, such as ethyl8-bromo-octanoate as disclosed in International Publication No. WO01/32596, which is hereby incorporated by reference, are prepared fromthe dicarboxylate alkylating agents of the present invention. Theprocess for converting the dicarboxylate compounds to the alkylatingagents of the prior art is often expensive and time consuming. Forexample, ethyl 8-bromo-octanoate is prepared from2-(6-bromohexyl)malonic acid diethyl ester by a multi-step process whichincludes an expensive distillation step. The process of the presentinvention reduces the number of synthetic steps required to preparealkylated salicylamides and, therefore, reduces their manufacturing costand time.

The present inventors have also discovered that dicarboxylic compoundshaving the formula

and salts thereof, wherein R¹, R², R³, R⁴, R⁵, and R⁷ are defined asabove, facilitate the delivery of active agents. According to apreferred embodiment, R⁷ is —(CH₂)_(n)—, where n is 4 to 10 and morepreferably 7 to 9. The terms “delivery agents” and “delivery agentcompounds” as used herein refer to the dicarboxylic compounds of thepresent invention and phenoxy alkanoic, alkenoic, and alkynoic acids andsalts thereof prepared by the method of the present invention.

One embodiment is a composition comprising at least one of the deliveryagent compounds and at least one active agent. These compositionsdeliver active agents to biological systems in increased or improvedbioavailability of the active agent compared to administration of theactive agent without the delivery agent compound.

Also provided are dosage unit forms comprising the compositions. Thedosage unit may be in the form of a liquid or a solid, such as a tablet,capsule or particle, including a powder or sachet.

Another embodiment is a method for administering an active agent to ananimal in need of the active agent, by administering a compositioncomprising at least one of the delivery agent compounds and the activeagent to the animal. Preferred routes of administration include theoral, intracolonic and pulmonary routes.

Yet another embodiment is a method of treating a disease or forachieving a desired physiological effect in an animal by administeringthe composition of the present invention.

Yet another embodiment is a method of preparing a composition of thepresent invention by mixing at least one delivery agent compound and atleast one active agent.

DETAILED DESCRIPTION OF THE INVENTION

The terms “alkyl”, “alkenyl”, and “alkynyl” (and also “alkylene”,“alkenylene”, and “alkynylene”) as used herein include linear andbranched alkyl, alkenyl, and alkynyl substituents, respectively.

The term “substituted” as used herein refers to compounds substitutedwith one or more of C₁-C₄ alkyl, C₂-C₄ alkenyl, and C₂-C₄ alkynyl.

The term “phenoxy” as used herein refers to a moiety which contains aphenyl group bound to an oxygen atom. The phenyl group may besubstituted or unsubstituted.

Preferably, the oxygen atom of the phenoxy group of the phenoxycontaining compound is bound to a leaving group. Suitable phenoxycontaining compounds include, but are not limited to, compounds havingthe formula

where

R¹, R², R³, R⁴, and R⁵ are defined as above; and

R⁶ is a leaving group (e.g., H).

An example of a suitable phenoxy containing compound is1,4-dihydroxybenzene.

Alkylation

The phenoxy containing compound is alkylated with a dicarboxylatealkylating agent to form the dicarboxylated intermediate. Suitabledicarboxylate alkylating agents include, but are not limited to, thosehaving the formula

where

R⁷ is a linear or branched, C₁-C₂₀ alkylene, C₂-C₂₀ alkenylene, orC₂-C₂₀ alkynylene;

R⁷ is optionally substituted with C₁-C₄ alkyl, C₁-C₄ alkenyl, oxygen,nitrogen, sulfur, halogen, —OH, C₁-C₄ alkoxy, aryl, heteraryl, or vinyl;

R⁷ is optionally interrupted with aryl, heteroaryl, vinyl, oxygen,nitrogen, or sulfur;

R⁸ and R¹¹ are independently C₁-C₄ alkyl or C₁-C₄ haloalkyl; and

X is a suitable leaving group.

Suitable leaving groups include, but are not limited to, halogens andalcohols. Two preferred leaving groups are chlorine and bromine.Preferably, R⁸ and R¹¹ are independently C₁-C₄ alkyl. Preferably, R⁸ andR¹¹ are the same. R⁷ is preferably C₄-C₁₂ alkylene and more preferablyC₇-C₉ alkylene.

A preferred dicarboxylate alkylating agent has the formula

where

R²¹ and R²² are independently C₁-C₄ alkyl;

X is a suitable leaving group; and

n is an integer from 2 to 12.

Preferably, n ranges from 3 to 10, more preferably from 4 to 8, and mostpreferably from 6 to 8. Non-limiting examples of dicarboxylatealkylating agents include 2-(6-bromohexyl)-malonic acid diethyl esterand 2-(8-bromooctyl)malonic acid diethyl ester, which are available fromAllied Signal, Inc. of Morristown, N.J.

Many of the alkylating agents disclosed in the prior art, such as ethyl8-bromo-octanoate as disclosed in International Publication No. WO01/32596, are prepared from the dicarboxylate alkylating agents of thepresent invention. The process for converting the dicarboxylatecompounds to the alkylating agents of the prior art is often expensiveand time consuming. For example, ethyl 8-bromo-octanoate is preparedfrom 2-(6-bromohexyl)malonic acid diethyl ester by a multi-step processwhich includes an expensive distillation step. The process of thepresent invention reduces the number of synthetic steps required toprepare alkylated salicylamides and, therefore, reduces theirmanufacturing cost and time.

The reaction between the dicarboxylate alkylating agent and the phenoxycontaining compound is preferably carried out in the presence of aslight molar excess of phenoxy containing compound relative todicarboxylate alkylating agent. Generally, the molar ratio of phenoxycontaining compound to dicarboxylate alkylating agent ranges from about1:1 to about 1:0.5, preferably from about 1:0.99 to about 1:0.8, andmost preferably about 1:0.95.

The alkylating reaction is preferably performed in the presence of asuitable base, such as pyridine, picoline, tetramethylguanidine,triethylamine, diisopropylethylamine, sodium or potassium bicarbonate,sodium or potassium carbonate, or any combination of any of theforegoing. According to a preferred embodiment, the base is sodiumcarbonate. Generally, the reaction is performed in the presence of aslight molar excess of base relative to the phenoxy containing compound.

The reaction may be carried out in solvents including, but not limitedto, dimethylacetamide (DMAC); dimethylformamide (DMF); ketones, such asacetone, methylethylketone, and methylisobutylketone; and anycombination of any of the foregoing. Preferably, the solvent isnon-aqueous.

The alkylating reaction is generally performed at a temperature of fromabout 40 to about 80° C. The reaction is preferably performed at atemperature of from about 60 to about 80° C. and most preferably atabout 70° C. The reaction is typically performed at atmospheric pressureto full vacuum and preferably from about 22 to about 24″ Hg of vacuum.

The reaction mixture prior and during the reaction preferably containsless than 5%, more preferably less than 3%, and most preferably lessthan 1% by weight of water, based upon 100% total weight of reactionmixture.

The reaction is generally performed for a time sufficient to ensure thecomplete reaction of the alkylating agent. The reaction duration mayvary depending on the starting materials. Generally, the reaction isallowed to run for a time sufficient so that at least about 90% andpreferably at least about 99% of the limiting reagent, i.e., thedicarboxylate alkylating agent, has been consumed, but is stopped beforesignificant side reaction product builds up. This reduces or eliminatesthe need for purification of the final product. According to oneembodiment, the reaction is performed for from about 2 to about 18hours, more preferably from about 3 to about 5 hours, and mostpreferably about 4 hours.

The dicarboxylated intermediate has the formula

where R¹, R², R³, R⁴, R⁵, R⁷, R⁸ and R¹¹ are defined as above.

The dicarboxylated intermediate is then, optionally, hydrolyzed anddecarboxylated to yield the phenoxy alkanoic, alkenoic, or alkynoic acidor salt thereof. The hydrolysis step may be performed before or afterthe decarboxylation. According to a preferred embodiment, thedecarboxylation is performed after hydrolysis. Typically, this processentails the removal of one of the carboxylate moieties. Optionally, thecarboxylate moiety or moieties of the alkylated phenoxy containingcompound may be hydrolyzed to form a carboxylic acid moiety orcarboxylic acid moieties or carboxylate salt. One of the carboxylategroups may be removed and the remaining carboxylate group may behydrolyzed by acidic, basic and/or neutral hydrolysis as known in theart. Neutral hydrolysis may be performed, for example, with super-heatedwater at a temperature of from about 100 to about 250° C.

Hydrolysis

Optionally, the phenoxy alkanoic, alkenoic, or alkynoic acid orcarboxylate derivative thereof may be further reacted to modify the endgroup of the alkylating moiety, i.e., R⁸ or R¹¹. For example, the endgroup —CN or —C(O)O—CH₂—CH₃ may be modified to —COOH or a salt thereof.This maybe accomplished by methods known in the art, such asneutralization and acidic, basic, and neutral hydrolysis.

Decarboxylation

If a monocarboxylic phenoxy containing compound is desired, the prepareddicarboxylate intermediate may be decarboxylated. The decarboxylationstep is performed either before or after the optional hydrolysis step.Preferably, decarboxylation is performed after the deprotecting anddeactivating steps and optional hydrolysis step.

The decarboxylation step removes one of the carboxylate moieties fromthe dicarboxylated intermediate (i.e. one of the two carboxyl groups atthe end of the chain R⁷). Decarboxylation can be performed by any methodknown in the art, such as acidic hydrolysis. Acidic hydrolysis may beperformed, for example, with aqueous hydrochloric acid or aqueoustrifluoroacetic acid. For example, acidic hydrolysis may be performedwith aqueous hydrochloric acid in acetone at a temperature of from about25 to about 65° C. According to one embodiment, acidic hydrolysis isperformed at a pH of about 3.5 to 4.5 and preferably at about 4. Inorder to control foaming due to the release of carbon dioxide, thereaction may be performed in the presence of acetone.

Decarboxylation can also be performed by heating the dicarboxylatedintermediate in a high boiling point organic solvent, such as xylenes,toluene, heptane, dimethyl acetamide (DMA or DMAC), dimethyl formamide(DMF), methyl sulfoxide, isoparaffins (e.g. isopar-G, isopar-H,isopar-L, and isopar-K available from Exxon Chemicals of Houston, Tex.),and any combination of the foregoing. The organic solvent preferably hasa boiling point of at least 110° C. and more preferably of at least 140°C. According to one embodiment, the decarboxylation reaction ispreferably performed at a temperature ranging from about 120 to about160° C., more preferably from about 140 to about 160° C., and mostpreferably from about 145 to about 165° C. The temperature at which thereaction is performed should be sufficient to remove one of thecarboxylate groups at the end of the chain R⁷.

Preferably, any water in the reaction mixture is removed prior toheating. Water may be removed from a reaction mixture containing thefree acid of the dicarboxylated intermediate (which is formed if thedicarboxylated intermediate is hydrolyzed as described in the“Hydrolysis” section above) as follows. The free acid is mixed with anorganic solvent in which it is soluble, such as xylenes. The aqueouslayer is then extracted, which in this case is the lower layer, leavingthe free acid in xylenes. The reaction mixture may then be heated todecarboxylate the free acid of the dicarboxylated intermediate.

The reaction mixture prior and during the decarboxylation reactionpreferably contains less than 5%, more preferably less than 3%, and mostpreferably less than 1% by weight of water, based upon 100% total weightof reaction mixture.

The decarboxylation step may also be performed neat (i.e. without asolvent) by heating the dicarboxylated intermediate (or free acidthereof) to a temperature ranging from about 140 to about 200° C.

The hydrolyzing and decarboxylating steps maybe performed at atemperature of from about 20 to about 200° C.

Suitable solvents for the alkylated phenoxy containing compound in thedecarboxylating and hydrolyzing steps include, but are not limited to,organic solvents, such as ethanol, dimethylacetamide (DMAC),dimethylformamide (MDW), ketones (e.g. acetone, methylethylketone, andmethylisobutylketone), and any combination of any of the foregoing.

Salts of the alkylated phenoxy containing compound may be formed by anymethod known in the art. For example, the acid form of the alkylatedphenoxy containing compound, i.e., where the alkylated phenoxycontaining compound has a —COOH moiety, may be converted into thecorresponding sodium salt by reacting it with sodium hydroxide. Suitablesalts include, but are not limited to, organic and inorganic salts, forexample alkali-metal salts, such as sodium, potassium and lithium;alkaline-earth metal salts, such as magnesium, calcium or barium;ammonium salts; basic amino acids, such as lysine or arginine; andorganic amines, such as dimethylamine or pyridine. Sodium salts include,but are not limited to, mono-, di-, and other multi-valent sodium salts.A preferred salt is the disodium salt. The salts may also be solvates,including ethanol solvates, and hydrates. The term “solvate” as usedherein includes, but is not limited to, a molecular or ionic complex ofmolecules or ions of a solvent, such as ethanol, with ions or moleculesof the compounds of the present invention.

The present method maybe used to prepare phenoxy alkanoic, alkenoic, andalkynoic acids and salts thereof having the formula

where

R¹, R², R³, R⁴, R⁵, and R⁷ are defined as above.

The alkylated phenoxy containing compounds of the present invention maybe isolated and/or purified by methods known in the art. For example,the alkylated phenoxy containing compounds may be purified byrecrystallization or fractionation on one or more chromatographicsupports. Fractionation may be performed on suitable chromatographicsupports, such as silica gel or alumina, using solvent mixtures such asacetic acid/butanol/water as the mobile phase; reverse phase columnsupports using trifluoroacetic acid/acetonitrile mixtures as the mobilephase; and ion exchange chromatography using water as the mobile phase.The alkylated phenoxy containing compounds may also be purified toremove impurities, such as inorganic salts, by extraction with a loweralcohol, such as methanol, butanol, or isopropanol.

The method of the present invention uses readily available andinexpensive starting materials and provides a cost-effective method forpreparing and isolating alkylated phenoxy containing compounds. Themethod is simple to perform and is amenable to industrial scale-up forcommercial production.

ACTIVE AGENT DELIVERY SYSTEMS

Dicarboxylate Delivery Agent Compounds

The dicarboxylate delivery agent compounds of the present inventioninclude the free acids of the dicarboxylated intermediates of thepresent invention (i.e. when R⁸ and R¹¹ are hydrogen) and salts thereof.Suitable salts include, but are not limited to, organic and inorganicsalts, for example alkali-metal salts, such as sodium, potassium andlithium; alkaline-earth metal salts, such as magnesium, calcium orbarium; ammonium salts; basic amino acids, such as lysine or arginine;and organic amines, such as dimethylamine or pyridine. Preferably, thesalts are sodium salts. The salts may be mono- or multi-valent salts,such as monosodium salts, di-sodium salts, and trisodium salts. Thesalts may,also be solvates, including ethanol solvates, and hydrates.

The delivery agent compounds may be in the form of the free amine orsalts thereof. Suitable salts include, but are not limited to, organicand inorganic salts, for example hydrochloride salts, acetate orcitrate.

Salts of the delivery agent compounds of the present invention may beprepared by methods known in the art. For example, sodium salts may beprepared by dissolving the delivery agent compound in ethanol and addingaqueous sodium hydroxide. In addition, poly amino acids and peptidescomprising one or more of these compounds may be used. An amino acid isany carboxylic acid having at least one free amine group and includesnaturally occurring and synthetic amino acids. Poly amino acids areeither peptides (which are two or more amino acids joined by a peptidebond) or are two or more amino acids linked by a bond formed by othergroups which can be linked by, e.g., an ester or an anhydride linkage.Peptides can vary in length from dipeptides with two amino acids topolypeptides with several hundred amino acids. One or more of the aminoacids or peptide units may be acylated or sulfonated.

Active Agents

Active agents suitable for use in the present invention includebiologically active agents and chemically active agents, including, butnot limited to, pesticides, pharmacological agents, and therapeuticagents.

For example, biologically or chemically active agents suitable for usein the present invention include, but are not limited to, proteins;polypeptides; peptides; hormones; polysaccharides, and particularlymixtures of muco-polysaccharides; carbohydrates; lipids; small polarorganic molecules (i.e. polar organic molecules having a molecularweight of 500 daltons or less); other organic compounds; andparticularly compounds which by themselves do not pass (or which passonly a fraction of the administered dose) through the gastro-intestinalmucosa and/or are susceptible to chemical cleavage by acids and enzymesin the gastro-intestinal tract; or any combination thereof.

Further examples include, but are not limited to, the following,including synthetic, natural or recombinant sources thereof: growthhormones, including human growth hormones (hGH), recombinant humangrowth honnones (rhGH), bovine growth honnones, and porcine growthhormones; growth hormone releasing hormones; growth hormone releasingfactor, interferons, including α, β and γ, interleukin-1; interleukin-2;insulin, including porcine, bovine, human, and human recombinant,optionally having counter ions including zinc, sodium, calcium andammonium; insulin-like growth factor, including IGF-1; heparin,including unfractionated heparin, heparinoids, dermatans, chondroitinis,low molecular weight heparin, very low molecular weight heparin andultra low molecular weight heparin; calcitonin, including salmon, eel,porcine and human; erythropoietin; atrial naturetic factor; antigens;monoclonal antibodies; somatostatin; protease inhibitors;adrenocorticotropin, gonadotropin releasing hormone; oxytocin;leutinizing-honione-releasinig-hormone; follicle stimulating hormone;glucocerebrosidase; thrombopoietin; filgrastim; prostaglandins;cyclosporin; vasopressin; cromolyn sodium (sodium or disodiumchronioglycate); vancomycin; desferrioxamine (DFO); bisphosphonates,including alendronate, tiludronate, etidronate, clodronate, pamidronate,olpadronate, and incadronate; parathyroid hormone (PTH), including itsfragments; antimicrobials, including antibiotics, anti-bacterials andanti-fungal agents; vitamins; analogs, fragments, mimetics orpolyethylene glycol (PEG)-modified derivatives of these compounds; orany combination thereof. Non-limiting examples of antibiotics includegram-positive acting, bacteriocidal, lipopeptidal and cyclic peptidalantibiotics, such as daptomycin and analogs thereof. A preferred activeagent is calcitonin and more preferably salmon calcitonin.

The composition of the present invention comprises one or more deliveryagent compounds of the present invention, and one or more active agents.In one embodiment, one or more of the delivery agent compounds, or saltsof these compounds, or poly amino acids or peptides of which thesecompounds or salts form one or more of the units thereof, may be used asa delivery agent by mixing with the active agent prior to administrationto form an administration composition.

The administration compositions may be in the form of a liquid. Thesolution medium may be water (for example, for salmon calcitonin,parathyroid hormone, and erythropoietin), 25% aqueous propylene glycol(for example, for heparin) and phosphate buffer (for example, for rhGH).Other dosing vehicles include polyethylene glycol. Dosing solutions maybe prepared by mixing a solution of the delivery agent compound with asolution of the active agent, just prior to administration. Alternately,a solution of the delivery agent compound (or active agent) may be mixedwith the solid form of the active agent (or delivery agent compound).The delivery agent compound and the active agent may also be mixed asdry powders. The delivery agent compound and the active agent can alsobe admixed during the manufacturing process.

The dosing solutions may optionally contain additives such as phosphatebuffer salts, citric acid, glycols, or other dispersing agents.Stabilizing additives may be incorporated into the solution, preferablyat a concentration ranging between about 0.1 and 20% (w/v).

The administration compositions may alternately be in the form of asolid, such as a tablet, capsule or particle, such as a powder orsachet. Solid dosage forms may be prepared by mixing the solid form ofthe compound with the solid form of the active agent.

Alternately, a solid may be obtained from a solution of compound andactive agent by methods known in the art, such as freeze-drying(lyophilization), precipitation, crystallization and solid dispersion.

The administration compositions of the present invention may alsoinclude one or more enzyme inhibitors. Such enzyme inhibitors include,but are not limited to, compounds such as actinonin or epiactinonin andderivatives thereof. Other enzyme inhibitors include, but are notlimited to, aprotinin (Trasylol) and Bowman-Birk inhibitor.

The amount of active agent used in an administration composition of thepresent invention is an amount effective to accomplish the purpose ofthe particular active agent for the target indication. The amount ofactive agent in the compositions typically is a pharmacologically,biologically, therapeutically, or chemically effective amount. However,the amount can be less than that amount when the composition is used ina dosage unit form because the dosage unit form may contain a pluralityof delivery agent compound/active agent compositions or may contain adivided pharmacologically, biologically, therapeutically, or chemicallyeffective amount. The total effective amount can then be administered incumulative units containing, in total, an effective amount of the activeagent.

The total amount of active agent to be used can be determined by methodsknown to those skilled in the art. However, because the compositions ofthe invention may deliver active agents more efficiently thancompositions containing the active agent alone, lower amounts ofbiologically or chemically active agents than those used in prior dosageunit forms or delivery systems can be administered to the subject, whilestill achieving the same blood levels and/or therapeutic effects.

The presently disclosed delivery agent compounds facilitate the deliveryof biologically and chemically active agents, particularly in oral,intranasal, sublingual, intraduodenal, subcutaneous, buccal,intracolonic, rectal, vaginal, mucosal, pulmonary, transdermal,intradermal, parenteral, intravenous, intramuscular and ocular systems,as well as traversing the blood-brain barrier.

Dosage unit forms can also include any one or combination of excipients,diluents, disintegrants, lubricants, plasticizers, colorants,flavorants, taste-masking agents, sugars, sweeteners, salts, and dosingvehicles, including, but not limited to, water, 1,2-propane diol,ethanol, olive oil, and any combination thereof.

The delivery agent compounds and compositions of the subject inventionare useful for administering biologically or chemically active agents toany animals, including but not limited to birds such as chickens;mammals, such as rodents, cows, pigs, dogs, cats, primates, andparticularly humans; and insects.

The system is particularly advantageous for delivering chemically orbiologically active agents that would otherwise be destroyed or renderedless effective by conditions encountered before the active agent reachesits target zone (i.e. the area in which the active agent of the deliverycomposition is to be released) and within the body of the animal towhich they are administered. Particularly, the compounds andcompositions of the present invention are useful in orally administeringactive agents, especially those that are not ordinarily orallydeliverable, or those for which improved delivery is desired.

The compositions comprising the delivery agent compounds and activeagents have utility in the delivery of active agents to biologicalsystems and in an increased or improved bioavailability of the activeagent compared to administration of the active agent without thedelivery agent. Delivery can be improved by delivering more active agentover a period of time, or in delivering active agent in a particulartime period (such as to effect quicker or delayed delivery), or indelivering the active agent at a specific time, or over a period of time(such as sustained delivery).

Another embodiment of the present invention is a method for thetreatment or prevention of a disease or for achieving a desiredphysiological effect, such as those listed in the table below, in ananimal by administering the composition of the present invention.Specific indications for active agents can be found in the Physicians'Desk Reference (54^(th) Ed., 2000, Medical Economics Company, Inc.,Montvale, N.J.), which is herein incorporated by reference. The activeagents in the table below include their analogs, fragments, mimetics,and polyethylene glycol-modified derivatives.

Active Agent Disease and Physiological Effect Growth hormones Growthdisorders Interferons, including Viral infection, including chroniccancer α, β and γ. and multiple sclerosis Interleukin-1; interleukin-2.Viral infection; cancer Insulin; Insulin-like Diabetes growth factorIGF-S1. Heparin Thrombosis; prevention of blood coagulation Calcitonin.Osteoporosis; diseases of the bone Erythropoietin Anemia Atrialnaturetic factor Vasodilation Antigens Infection Monoclonal antibodiesTo prevent graft rejection; cancer Somatostatin Bleeding ulcer; erosivegastritis Protease inhibitors AIDS Adrenocorticotropin High cholesterol(to lower cholesterol) Gonadotropin releasing Ovulatory disfunction (tostimulate hormone ovulation) Oxytocin Labor disfunction (to stimulatecontractions) Leutinizing-hormone- Regulate reproductive functionreleasing-hormone; follicle stimulating hormone GlucocerebrosidaseGaucher disease (to metabolize lipoprotein) ThrombopoietinThrombocytopenia Filgrastim Reduce infection in chemotherapy patientsProstaglandins Hypertension Cyclosporin Transplant rejection VasopressinBed-wetting; antidiuretic Cromolyn sodium; Asthma; allergies VancomycinDesferrioxamine (DFO) Iron overload Parathyroid hormone (PTH),Osteoporosis; Diseases of the bone including its fragments.Antimicrobials Infection including gram-positive bacterial infectionVitamins Vitamin deficiencies Bisphosphonates Osteoporosis; Paget'sdisease; Inhibits osteoclasts

For example, one embodiment of the present invention is a method fortreating a patient suffering from or susceptible to diabetes byadministering insulin and at least one of the delivery agent compoundsof the present invention.

Following administration, the active agent present in the composition ordosage unit form is taken up into the circulation. The bioavailabilityof the agent is readily assessed by measuring a known pharmacologicalactivity in blood, e.g., an increase in blood clotting time caused byheparin, or a decrease in circulating calcium levels caused bycalcitonin. Alternately, the circulating levels of the active agentitself can be measured directly.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention will now be illustrated in the following non-limitingexample which is illustrative of the invention but is not intended tolimit the scope of the invention. All percentages are by weight unlessotherwise indicated.

EXAMPLE 1

A disodium salt of a phenoxy carboxylic acid compound can be prepared bythe procedure shown in the flow chart below.

All patents, patent applications, literature publications, and testmethods cited herein are hereby incorporated by reference.

Many variations of the present invention will suggest themselves tothose skilled in the art in light of the above detailed disclosure. Allsuch modifications are within the full intended scope of the appendedclaims.

1. A method of preparing an alkylated phenoxy containing compound from aphenoxy containing compound, the method comprises the steps of (a)alkylating the phenoxy containing compound with a dicarboxylatealkylating agent to form a dicarboxylated phenoxy containing compound,and (b) decarboxylating the dicarboxylated phenoxy containing compoundto form the alkylated phenoxy containing compound, wherein thedicarboxylate alkylating agent has the formula

wherein R⁷ is a linear or branched C₇-C₁₂ alkylene; R⁷ is optionallysubstituted with C₁-C₄ alkyl, C₁-C₄ alkenyl, oxygen, nitrogen, sulfur,halogen, —OH, C₁-C₄ alkoxy, aryl, heteraryl, or vinyl; R⁷ is optionallyinterrupted with aryl, heteroaryl, vinyl, oxygen, nitrogen, or sulfur;R⁸ and R¹¹ are independently C₁-C₄ alkyl or C₁-C₄ haloalkyl; and X is asuitable leaving group.
 2. The method of claim 1, wherein the molarratio of phenoxy containing compound to dicarboxylate alkylating agentis from about 1:1 to about 1:0.5.
 3. The method of claim 1, wherein thealkylating step is performed in the presence of a base.
 4. The method ofclaim 3, wherein the molar ratio of base to phenoxy containing compoundis greater than
 1. 5. The method of claim 4, wherein the base ispyridine, picoline, tetramethylguanidine, triethylamine,diisopropylethylamine, sodium bicarbonate, potassium bicarbonate, sodiumcarbonate, potassium carbonate, or any combination of any of theforegoing.
 6. The method of claim 5, wherein the base is sodiumcarbonate.
 7. The method of claim 1, wherein the alkylating step isperformed at a temperature of from about 40 to about 80° C.
 8. Themethod of claim 7, wherein the alkylating step is performed at atemperature of from about 60 to about 80° C.
 9. The method of claim 1,further comprising hydrolyzing one or more carboxyl moieties of thealkylated phenoxy carboxylic acid compound after step (a) to form thefree acid of the alkylated phenoxy carboxylic acid compound.
 10. Themethod of claim 9, wherein the decarboxylating step is performed afterthe hydrolyzing step.
 11. The method of claim 1, wherein decarboxylatingcomprises heating the dicarboxylated phenoxy containing compound in anorganic solvent to a temperature ranging from about 140 to about 200° C.12. The method of claim 11, wherein the organic solvent has a boilingpoint of at least about 110° C.
 13. The method of claim 11, wherein theorganic solvent is selected from xylenes, toluene, heptane, dimethylacetamide, dimethyl formamide, methyl sulfoxide, isoparaffins, and anycombination of any of the foregoing.
 14. A method of preparing analkylated phenoxy containing compound from a dicarboxylated phenoxycontaining compound comprising the step of decarboxylating andhydrolyzing the dicarboxylated phenoxy containing compound to form thealkylated phenoxy containing compound, wherein the dicarboxylatedphenoxy containing compound has the formula

where R¹, R², R³, and R⁴ are independently H, —OH, halogen, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₁-C₄ alkoxy, —C(O)R¹², —NO₂, —NR⁹R¹⁰, or —N⁺R⁹R¹⁰R¹³(R¹⁴)⁻; R⁵ is H, —OH, —NO₂, halogen, —CF₃, —R¹⁵R¹⁶, —N⁺R¹⁵R¹⁶R¹⁷ (R¹⁸)⁻,amide, C₁-C₁₂ alkoxy, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, carbamate,carbonate, urea, or —C(O)R¹⁹; R⁷ is a linear or branched C₁-C₂₀alkylene, C₂-C₂₀ alkenylene, or C₂-C₂₀ alkynylene; R⁷ is optionallysubstituted with C₁-C₄ alkyl, C₁-C₄ alkenyl, oxygen, nitrogen, sulfur,halogen, —OH, C₁-C₄ alkoxy, aryl, heteraryl, or vinyl; R⁷ is optionallyinterrupted with aryl, heteroaryl, vinyl, oxygen, nitrogen, or sulfur;R⁸ and R¹¹ are independently C₁-C₄ alkyl or C₁-C₄ haloalkyl; R⁹, R¹⁰,and R¹³ are independently H or C₁-C₁₀ alkyl; R¹² is H, C₁-C₄ alkyl,C₂-C₄ alkenyl, or —NH₂; R¹⁴ and R¹⁸ are independently a halide,hydroxide, sulfate, tetrafluoroborate, or phosphate; R¹⁵, R¹⁶, and R¹⁷are independently H, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl substituted with —COOH,C₂-C₁₂ alkenyl, C₂-C₁₂ alkenyl substituted with —COOH, —C(O)R²⁰; R¹⁹ is—H, C₁-C₆ alkyl, or C₂-C₁₂ alkenyl; and R²⁰ is —OH, C₁-C₁₀ alkyl, orC₂-C₁₂ alkenyl, wherein at least one of R¹, R², R³, R⁴ and R⁵ is —OH oralkoxy.
 15. The method of claim 1, wherein R⁷ is a linear or branchedC₇-C₉ alkylene.
 16. A method of preparing an alkylated phenoxycontaining compound from a phenoxy containing compound, the methodcomprises the steps of (a) alkylating the phenoxy containing compoundwith a dicarboxylate alkylating agent to form a dicarboxylated phenoxycontaining compound, and (b) decarboxylating the dicarboxylated phenoxycontaining compound to form the alkylated phenoxy containing compound,wherein the phenoxy containing compound has the formula

wherein R¹, R², R³, and R⁴ are independently H, —OH, halogen, C₁-C₄alkyl, C₂-C₄ alkenyl, C₁-C₄ alkoxy, —C(O)R¹², —NO₂, —NR⁹R¹⁰, or—N⁺R⁹R¹⁰R¹³ (R¹⁴)⁻; R⁵ is H, —OH, —NO₂, halogen, —CF₃, —R¹⁵R¹⁶,—N⁺R¹⁵R¹⁶R¹⁷ (R¹⁸)⁻, amide, C₁-C₁₂ alkoxy, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl,carbamate, carbonate, urea, or —C(O)R¹⁹; R⁶ is a leaving group; R⁹, R¹⁰,and R¹³ are independently H or C₁-C₁₀ alkyl; R¹² is H, C₁-C₄ alkyl,C₂-C₄ alkenyl, or —NH₂; R¹⁴ and R¹⁸ are independently a halide,hydroxide, sulfate, tetrafluoroborate, or phosphate; R¹⁵, R¹⁶, and R¹⁷are independently H, C₁-C₁₀alkyl, C₁-C₁₀ alkyl substituted with —COOH,C₂-C₁₂ alkenyl, C₂-C₁₂ alkenyl substituted with —COOH, —C(O)R²⁰; R¹⁹ is—H, C₁-C₆ alkyl, or C₂-C₁₂ alkenyl; and R²⁰ is —OH, C₁-C₁₀ alkyl, orC₂-C₁₂ alkenyl, wherein at least one of R¹, R², R³, R⁴ and R⁵ is —OH oralkoxy.
 17. The method of claim 16, wherein the dicarboxylate phenoxycontaining compound has the formula

where R¹, R², R³, and R⁴ are independently H, —OH, halogen, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₁-C₄ alkoxy, —C(O)R¹², —NO₂, —NR⁹R¹⁰, or —N⁺R⁹R¹⁰R¹³(R¹⁴)—; R⁵ is H, —OH, —NO₂, halogen, —CF₃, —R¹⁵R¹⁶, —N⁺R¹⁵R¹⁶R¹⁷ (R¹⁸)⁻,amide, C₁-C₁₂ alkoxy, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, carbamate,carbonate, urea, or —C(O)R¹⁹; R⁷ is a linear or branched, C₁-C₂₀alkylene, C₂-C₂₀ alkenylene, or C₂-C₂₀ alkynylene; R⁷ is optionallysubstituted with C₁-C₄ alkyl, C₁-C₄ alkenyl, oxygen, nitrogen, sulfur,halogen, —OH, C₁-C₄ alkoxy, aryl, heteraryl, or vinyl; R⁷ is optionallyinterrupted with aryl, heteroaryl, vinyl, oxygen, nitrogen, or sulfur;R⁸ and R¹¹ are independently C₁-C₄ alkyl or C₁-C₄ haloalkyl; R⁹, R¹⁰,and R¹³ are independently H or C₁-C₁₀ alkyl; R¹² is H, C₁-C₄ alkyl,C₂-C₄ alkenyl, or —NH₂; R¹⁴ and R¹⁸ are independently a halide,hydroxide, sulfate, tetrafluoroborate, or phosphate; R¹⁵, R¹⁶, and R¹⁷are independently H, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl substituted with —COOH,C₂-C₁₂ alkenyl, C₂-C₁₂ alkenyl substituted with —COOH, —C(O)R²⁰; R¹⁹ is—H, C₁-C₆ alkyl, or C₂-C₁₂ alkenyl; and R²⁰ is —OH, C₁-C₁₀ alkyl, orC₂-C₁₂ alkenyl, wherein at least one of R¹, R², R³, R⁴ and R⁵ is —OH oralkoxy.
 18. The method of claim 16, wherein the alkylated phenoxycontaining compound has the formula

where R¹, R², R³, and R⁴ are independently H, —OH, halogen, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₁-C₄ alkoxy, —C(O)R¹², —NO₂, —NR⁹R¹⁰, or —N⁺R⁹R¹⁰R¹³(R¹⁴)⁻; R⁵ is H, —OH, —NO₂, halogen, —CF₃, —R¹⁵R¹⁶, —N⁺R¹⁵R¹⁶R¹⁷ (R¹⁸)⁻,amide, C₁-C₁₂ alkoxy, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, carbamate,carbonate, urea, or —C(O)R¹⁹; R⁷ is a linear or branched, C₁-C₂₀alkylene, C₂-C₂₀ alkenylene, or C₂-C₂₀ alkynylene; R⁷ is optionallysubstituted with C₁-C₄ alkyl, C₁-C₄ alkenyl, oxygen, nitrogen, sulfur,halogen, —OH, C₁-C₄ alkoxy, aryl, heteraryl, or vinyl; R⁷ is optionallyinterrupted with aryl, heteroaryl, vinyl, oxygen, nitrogen, or sulfur;R⁹, R¹⁰, and R¹³ are independently H or C₁-C₁₀ alkyl; R¹² is H, C₁-C₄alkyl, C₂-C₄ alkenyl, or —NH₂; R¹⁴ and R¹⁸ are independently a halide,hydroxide, sulfate, tetrafluoroborate, or phosphate; R¹⁵, R¹⁶, and R¹⁷are independently H, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl substituted with —COOH,C₂-C₁₂ alkenyl, C₂-C₁₂ alkenyl substituted with —COOH, —C(O)R²⁰; R¹⁹ is—H, C₁-C₆ alkyl, or C₂-C₁₂ alkenyl; and R²⁰ is —OH, C₁-C₁₀ alkyl, orC₂-C₁₂ alkenyl, wherein at least one of R¹, R², R³, R⁴ and R⁵ is —OH oralkoxy.